Pemvidutide gains MOMENTUM in phase II obesity trial

Pemvidutide, an investigational, peptide-based GLP-1/glucagon dual receptor agonist, gains traction in the booming obesity drug market, delivering significant weight loss reductions in nondiabetic individuals with overweight or obesity in the phase II MOMENTUM trial.

“There was a robust mean weight loss of 15.6 percent … and over 30 percent of participants on pemvidutide 2.4 mg lost ≥20 percent body weight at week 48,” said Dr Louis Aronne from Weill Cornell Medicine, New York City, New York, US, at ADA 2024.

The mean weight loss translated to 32.2 pounds. The maximal weight loss achieved was a staggering 87.1 pounds. [ADA 2024, abstract 262-OR]

The curve of the 2.4-mg dose dipped by week 4 and continued to slope down up to week 48. This, according to Aronne, could signal the possibility of greater weight loss with a longer treatment duration.

With placebo, the mean weight loss was only 2.2 percent. A comparison between the pemvidutide 2.4-mg and placebo arms yielded a p value of <0.001.

Individuals with elevated serum lipids at baseline had substantial and clinically meaningful reductions in triglycerides (TG; 56 percent vs 13 percent; p<0.001), total cholesterol (TC; 20 percent vs 4 percent; p<0.001), and low-density lipoprotein (LDL; 17 percent vs 2 percent; p<0.05) with pemvidutide 2.4 mg vs placebo at week 48.

Week 48 also saw improved blood pressure (BP) with pemvidutide 2.4 mg without clinically meaningful increases in heart rate (least squares mean [LSM] change from baseline, -4.6 [systolic] and -2.9 mm Hg [diastolic]).

Lower doses also fared well

The 1.2- and 1.8-mg pemvidutide doses are not without benefit, generating mean weight losses of 10.3 and 11.2 percent, respectively, by week 48. While the dips in the curves were not as deep as the 2.4-mg dose, the weight drop was consistent until week 48. The comparisons against placebo also yielded p values of <0.001 for both doses.

The 1.2-mg dose also rendered reductions in TG (36 percent; p<0.05 [vs placebo]), TC (15 percent; p<0.005), and LDL (12 percent) at week 48. A similar pattern was seen with the 1.8-mg dose (33 percent; p<0.05 [TG], 18 percent; p<0.001 [TC], and 22 percent; p<0.005 [LDL]).

Systolic BP dropped with both 1.2- and 1.8-mg doses (LSM change from baseline, -2.3 and -1.6 mm Hg), as did diastolic BP (LSM change from baseline, -2.1 and -1 mm Hg).

Safety profile

Most adverse events (AEs) were mild to moderate with only one drug-related serious AE (vomiting) reported with pemvidutide 2.4 mg. There were no AEs of special interest nor were there major adverse cardiac events across all pemvidutide arms.

Despite the higher rates of gastrointestinal AEs (nausea, vomiting, diarrhoea, constipation) with pemvidutide irrespective of dose, these were mostly mild to moderate in severity. These are also common with incretin-based agents, Aronne noted.

Lean mass loss implications

“One of the big issues [with weight loss] compounds … is the preservation of lean mass,” Aronne underscored. Lean mass loss of about 25 percent is an expected outcome of weight loss, but it is tied to an increase in mortality. [Exp Biol Med (Maywood) 2018;243:1275-1285]

Moreover, incretin-based therapy is associated with lean mass loss of up to 40 percent. [N Engl J Med 2021;384:989-1002] “[As such,] weight loss therapies that minimize loss of lean mass are needed,” he stressed.

“[Furthermore,] obesity is a multifactorial disease, and patients will need a variety of treatment options that fit their specific needs and comorbidities,” noted Aronne in a separate news report. [https://ir.altimmune.com/news-releases/news-release-details/altimmune-presents-data-phase-2-momentum-trial-pemvidutide, accessed July 1, 2024]

The team enrolled 391 nondiabetic individuals with obesity or overweight with at least one comorbidity (mean age 50 years, 76 percent women, mean BMI 37 kg/m², mean body weight 105 kg). Participants were randomized 1:1:1:1 to subcutaneous pemvidutide 1.2, 1.8, or 2.4 mg or placebo weekly for 48 weeks, along with standard lifestyle intervention (diet and exercise).

The 2.4-mg pemvidutide dose was titrated over 4 weeks, starting at 0.6 mg at week 1, 1.2 mg at week 2, 1.8 mg at weeks 3 and 4, and 2.4 mg from week 5 onwards. The two lower doses were not titrated.

Impressive lean mass preservation

In the MRI-based body composition analysis (n=50), the lean loss ratio with pemvidutide is only 21.9 percent. This implies that the weight loss may be attributable mainly to adipose mass loss.

“We are pleased with … the impressive lean mass preservation achieved with pemvidutide,” said Dr Vipin Garg, Altimmune President and Chief Executive Officer, in the news report. “[This] was better than [what has been] reported historically with diet and exercise programmes and greater than what has been publicly reported with other incretin weight loss drugs.”

“Preservation of lean mass, which is primarily muscle tissue, is believed to be important in maintaining healthy weight loss and physical function. We believe that the level of muscle preservation observed in [this] trial further adds to the differentiation of pemvidutide in the treatment of obesity,” added Garg.

“[Taken together,] these latest findings are particularly exciting, given that pemvidutide has not only demonstrated significant weight loss, but an impressive ability to preserve lean mass,” said Aronne.

“With its favourable safety profile to date and the potential to drive clinically meaningful improvements in other obesity-related conditions such as dyslipidaemia and hypertension, pemvidutide could offer a highly promising, long-term treatment option for multiple segments of the obese patient population to safely and effectively manage body weight,” Aronne added.